In this article, we’ll review data that persuaded the FDA to allow metformin to be studied in humans as the first anti-aging drug.1

Broad-Spectrum Effects

The most commonly prescribed antidiabetic drug is metformin. It has been in use in England since 1958 and in the United States since 1995.

Derived from a compound found in the French Lilac, metformin has a track record of safety and effectiveness at routine doses of up to 2,000 mg daily.4-7

So what evidence is there for the FDA to consider this drug as an anti-aging medication? The reason is simple:

Metformin can block or diminish many of the fundamental factors that accelerate aging.8-12

These include protecting against DNA damage glycation, poor mitochondrial function, and chronic inflammation. Metformin has been shown to facilitate DNA repair, which is critical for cancer prevention.

By attacking these fundamental degenerative processes, metformin can prevent the development of aging’s most troubling diseases.

Metformin has also been shown to increase the production of known longevity-promoting signaling molecules in cells, such as mTOR and AMPK—all of which reduce fat and sugar storage and increase youthful functioning at the cellular level.11,13

Studies have shown that by activating AMPK, metformin specifically impacts lifespan. For example, roundworms treated with metformin have higher AMPK activity and live about 20% longer than untreated control animals.14 Mice treated with metformin have been found to live nearly 6% longer than controls.11 And most impressively, diabetics taking metformin were shown to live 15% longer than healthy individuals without diabetes!15

AMPK activity declines with age,16 making us more vulnerable to many of the diseases associated with aging. Fortunately, a wealth of recent studies show that by activating AMPK, metformin plays a major role in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

By combatting many of the underlying causes of aging—and by activating AMPK—metformin can be considered a broad-spectrum anti-aging drug.

WHAT YOU NEED TO KNOW

Metformin as an Anti-Aging Drug

Metformin has been a staunch workhorse against diabetes for more than 50 years.

Studies show that metformin acts by boosting the activity of AMPK, a master metabolic regulator that favors fat- and sugar-burning and prevents their accumulation.

Because AMPK is relevant in all tissues, this makes metformin extremely important in reducing metabolic imbalances in the entire body.

Strong evidence suggests that metformin, through its protective effects and AMPK-activating properties, can help prevent cancer, cardiovascular disease, obesity and its consequences, and even neurodegenerative disorders.

Cancer Protective Effects of Metformin

Diabetics have an increased risk of cancer. In a study of head and neck cancers, researchers were surprised to find that diabetic patients had a 46% reduction in risk of developing these cancers compared to non-diabetic patients.17 What was the reason for this unexpected reduction? The diabetic patients were taking metformin.

Similar effects have been seen for the risk of gastric (stomach) cancers as well, with metformin users experiencing a 55% decrease in the risk of stomach cancer compared with nonusers.18 Important studies like these have helped to confirm a decade-long trend suggesting that metformin has anti-cancer properties.17

While these studies show that metformin has the potential to reduce the risk of developing cancer, others show its benefits for those who already have cancer.

A study encompassing 27 clinical trials representing more than 24,000 patients found that in people with early-stage cancers of the colon and rectum, metformin use improved recurrence-free survival by 37%, overall survival by 31%, and cancer-specific survival by 42%.19

The same study reported similar results for men with early-stage prostate cancer, with metformin use increasing recurrence-free survival by 17%, overall survival by 18%, and cancer-free survival by 42% compared with non-metformin users.19

By now, metformin has been studied in the context of total tumor incidence in 17 different target organs, 21 strains of mice, and four strains of rats. It has been studied in cancers that occur spontaneously, and in those induced by 16 different chemical carcinogens from multiple classes, ionizing radiation, viruses, genetic modifications, and high-fat diets, using five different routes of administration.20

A whopping 86% of such studies showed that metformin clearly inhibited cancer development and showed zero evidence of cancer stimulation by the drug.20

Indeed, as one expert recently put it, maybe it’s time “to make this long story short” about metformin: It works to prevent cancer.20

Metformin Prevents Cardiovascular Disease

Despite billions of dollars spent on drugs such as Crestor and Lipitor, cardiovascular disease remains the single biggest killer in America. While there are multiple causes of cardiovascular disease, most boil down to the development of atherosclerosis, or “hardening of the arteries.”

Atherosclerosis is promoted by factors such as oxidation of LDL cholesterol, accumulation of that oxidized fat in arterial walls, and damage to the endothelium, which is the thin layer of cells lining those arterial walls.21

Metformin is now known to prevent these early steps in atherosclerosis development.

One of the key ways it does this is by activating the metabolic regulator AMPK. By activating AMPK, metformin:

Mitigates LDL oxidation and the resulting endothelial dysfunction, which slows the development of atherosclerosis.21

Reduces the conversion of harmless immune system cells (monocytes) into fat-laden macrophages, an action that reduces their accumulation in vessel walls.22 It also increases cholesterol export out of those cells, while also suppressing the inflammatory stimulus they normally produce.23,24

Offers critical protection to endothelial cells that line coronary arteries, which supply blood to the heart muscle itself. Specifically, metformin enhances the resistance of endothelial cells to “fat poisoning,” the death of endothelial cells in the presence of high fat concentrations.25 This is highly protective against heart attacks, which occur when coronary arteries, blocked by atherosclerotic plaques laden with fat and inflammatory cells, fail to provide enough blood to the hard-working heart muscle.

Metformin has also been shown to prevent the fragmentation of mitochondria in endothelial cells.26 Such fragmentation is closely associated with the dysfunction of endothelial cells and is now considered an important precursor of atherosclerosis.26

The results of these protective effects have been seen in numerous human studies. In one study, heart attack patients taking metformin had a significant 75% reduction in the risk of dying after 30 days, and a 68% reduction in their risk of dying 12 months after the attack.27

Several studies have also demonstrated that metformin reduces the risk of heart attack, and is associated with reduction in stroke, atrial fibrillation (an arrhythmia), and death from all causes.28

Finally, a 2016 study showed significant reductions in systolic (top number) blood pressure in nondiabetic people taking metformin. The largest reductions were seen in those having impaired glucose tolerance or obesity.29

Obesity itself appears ready to yield to metformin treatment, as we’ll now see.

FDA APPROVES FIRST ANTI-AGING STUDY

The FDA has approved a study that will determine if metformin can do more than lower blood sugar—it will evaluate metformin’s ability to slow aging. This is the first ever anti-aging study approved by the FDA.

Studies have shown that metformin can block or diminish many of the underlying factors that accelerate aging, and it has also been shown to extend lifespan in animals. Dr. Nir Barzilai from the Albert Einstein College of Medicine, along with researchers from the American Federation for Aging Research (AFAR), want to find out if metformin can extend lifespan in humans as well.

The study, called Targeting Aging with Metformin (TAME), will evaluate 3,000 people over a course of six years. Half of the participants will receive metformin, and the other half will receive a placebo. Since aging is largely characterized by the development of disease, the success of the study will be determined by whether or not the drug delays the onset of typical age-related diseases, such as cardiovascular disease, cancer, and cognitive decline.

This groundbreaking study has the potential to change the future of how we treat disease. Developing a single drug designed to treat multiple conditions would dramatically reduce the number of drugs a typical person would need, which would reduce overall drug side effects, eliminate contraindications, and of course, save money.

None of this is good for Big Pharma’s bottom line—which is likely why no company has agreed to fund the study. Until that happens, this important study is on hold.

But you can help. AFAR is seeking individual contributions to get the TAME study started. To learn more, and make a donation if you like, visit http://www.afar.org/donate/

Metformin Reduces Body Weight and Fat Mass

Metformin’s ability to activate AMPK makes it especially beneficial in combatting obesity. This is because AMPK is a metabolic regulator that stimulates youthful cellular behaviors such as burning fat (instead of storing it), taking sugar out of the blood, and recycling cellular contents to eliminate toxic proteins.30

As a result, metformin can be expected to have important effects on body weight and fat deposits. And indeed, studies show that metformin fights obesity and reduces body fat mass, even in non-diabetic patients.

This is true in some of the most challenging populations, such as women with polycystic ovary syndrome, a major cause of obesity and endocrine problems in premenopausal women.

In one study, women with polycystic ovary syndrome were treated with 850 mg of metformin or a placebo twice daily for 6 months. During that time, those in the placebo group experienced increases in weight and blood sugar, as expected. Those taking metformin, on the other hand, had significant decreases in weight and blood sugar—with metformin-treated women losing an average of 9.24 pounds. The metformin group also had significant increases in beneficial HDL cholesterol.31

Metformin has been found to significantly reduce body weight, body mass index (BMI), and insulin resistance in patients taking modern antipsychotic medications such as olanzapine, aripiprazole, risperidone, and quetiapine.32-35 These are impressive results, since major side effects of these drugs include rapid weight gain, loss of insulin sensitivity, and other features of metabolic syndrome.36

But by far, the largest group of people fighting obesity are simply aging individuals who are otherwise healthy (nondiabetic). Metformin shows promise for this population as well.

An important study in a group of such people—all women with midlife weight gain but normal blood sugars—showed that taking metformin for 12 months reduced mean body weight by 11.6 pounds.37 In addition, treated subjects had significant decreases in their body fat percentage, a favorable change that can reduce many of the long-term consequences of obesity.

Metformin is showing promise in obese but otherwise healthy young people as well. A group of 10-16- year-olds took 2,000 mg of metformin per day or a placebo for 18 months. Those taking metformin lost nearly half a pound in fat mass. By contrast, the placebo group gained almost 4.5 pounds in fat mass.38

Metformin as Neuroprotectant

There is rapidly growing literature on metformin’s potential role in preventing neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Once again, much of this literature focuses on metformin’s ability to activate AMPK, the youth-promoting energy regulator in all of our cells.

One major effect of AMPK activation is the cleanup of accumulated misfolded proteins in brain cells. The accumulation of proteins, such as tau and beta-amyloid, contributes to brain cell death and dysfunction in neurodegenerative diseases.

Thus, it makes sense that metformin might be effective in preventing disorders associated with those proteins. Numerous animal and laboratory studies show that metformin does indeed have such effects. These studies demonstrate that metformin:

Reduces levels of an enzyme that generates beta-amyloid proteins32

Decreases the harmful effect of beta-amyloid on brain cell function39-41

Reduces levels of alpha synuclein, another protein that accumulates and causes damage in Parkinson’s disease42

Prevents the loss of dopamine-producing brain cells in a model of Parkinson’s disease43,44

Improves motor coordination in a mouse model of Parkinson’s45

In 2016, a human study showed that taking 1,000 mg of metformin twice daily for 12 months improved memory recall in a group of older adults with a condition called amnestic mild cognitive impairment (a memory-stealing predecessor of Alzheimer’s).39

Given the close connections between Alzheimer’s and diabetes (it’s been called “Type III diabetes”), there is every reason to believe that metformin, through its AMPK-activating properties, will help in the long fight to retain our minds and personalities as we age.

PRECAUTIONS AND USEFUL SUGGESTIONS WITH METFORMIN USE

Although metformin has an outstanding track record in the fight against diabetes, cancer, obesity, neurodegenerative and cardiovascular diseases, there are some precautions to be aware of with its use.

Metformin is known to interfere with the absorption of B12, increasing the risk of vitamin B12 deficiency.46,47 Low B12 levels contribute to higher concentrations of artery-clogging homocysteine—an independent risk factor for cardiovascular disease.48,49 The tiny amounts of vitamin B12 and other B-vitamins found in commercial supplements is usually not enough to offset this problem. Individuals using metformin should ensure that they are taking higher doses of B-vitamins (at least 300 mcg of methylcobalamin, the active form of vitamin B12) and checking their homocysteine levels to ensure proper protection.

Some studies have shown that metformin reduces free and total testosterone levels in men.50Testosterone is especially important in male diabetics as it enhances insulin sensitivity.51 Life Extension has previously published clinical data on the importance of maintaining youthful testosterone levels in diabetic men to improve glucose utilization.52

If a blood test shows low testosterone, applying a topical testosterone cream can restore levels of this vital hormone to youthful ranges.

Side effects associated with metformin use include gastrointestinal distress or a slight taste disturbance, usually a metallic taste. Rarely, metformin may cause a potentially serious lactic acidosis, a buildup of lactic acid in the blood.53

If you use or are considering metformin, consult your physician, take your B-vitamins, and periodically check your kidney function, homocysteine levels, and in men, free and total testosterone.

Summary

The world’s first clinical trial of a true “anti-aging” drug may be about to begin. But while the study is new, the drug is more than half a century old.

Metformin has been used for more than 50 years to treat type II diabetes. A wealth of recent studies now supports a major role for metformin in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

The American Federation for Aging Research (AFAR) has a long uphill road to get this study (called TAME, or the Targeting Aging with Metformin trial) started. They face almost-certain opposition from Big Pharma companies for whom treating—not preventing—aging is a lucrative business.

The good news is that we don’t have to wait for this new metformin study to get off the ground. Metformin is already available as a prescription medication. And many thoughtful physicians who are presented with the evidence will prescribe it based on its recognized benefits against specific age-related disorders.

There are also nutrients that have been shown to boost AMPK activity and function to lower blood glucose similar to metformin.54-57

Long-term use of the popular diabetes drug metformin is linked with vitamin B12 deficiency and anemia, according to new research that solidifies some previous research.

“We have essentially confirmed what many smaller studies have suggested,” says Jill Crandall, MD, professor of clinical medicine at the Albert Einstein College of Medicine, the Bronx, who led the new study. “There is a small but significant risk of developing Vitamin B12 deficiency when people take metformin.”

The finding, she adds, ”has implications for the consequences of B12 deficiency.” These can include cognitive impairment, nerve problems (neuropathy) and anemia (low red blood cell count). B12 is crucial for the proper formation of red blood cells, for neurological functioning and for making DNA.

The link between taking the popular diabetes drug and deficiencies in vitamin B12 has been discussed as long ago as 1969, according to Dr. Crandall. However, few studies have looked at long term use, as her new study has done, tracking people for up to 13 years.

The new study was published online Feb. 22 in the Journal of Clinical Endocrinology & Metabolism.

Overview of the Metformin Study

The researchers evaluated more than 2,000 men and women enrolled in the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study. In these studies, researchers enrolled overweight people who had prediabetes (blood sugar levels higher than normal but not high enough to be termed diabetes) to see if modest weight loss or treatment with metformin could prevent or delay the onset of type 2 diabetes, then followed them to see if the effects endured.

Half of the participants were given 850 milligrams of metformin twice daily and half got placebo pills. At the 5-year mark, more of those in the metformin group than the placebo group had low B12 levels, affecting 4.3% of the metformin group but just 2.3% of the placebo group. However, the gap narrowed at 13 years, with 7.4% of the metformin group and 5.4% of the placebo group having low B12 at that point. The narrowed gap seems counter-intuitive until Dr. Crandall explains what is happening. “As time goes on, the groups are a little contaminated,” Dr. Crandall says, because some in the placebo group, as time went on, developed diabetes and had to begin taking metformin.

Years of use was linked with an increased risk of B12 deficiency, Dr. Crandall found. Those taking metformin were more likely to have anemia, regardless of their B12 status. Those taking metformin with low B12 were more likely to have neuropathy.

The study findings suggest that routine testing of Vitamin B12 should be considered in patients on metformin treatment, Dr. Crandall says. Experts think that metformin affects the way Vitamin B12 is absorbed by the body. “People should be aware of this possibility,” Dr. Crandall says of the metformin and low B12 link. Currently, she says, there are no official recommendations for B12 testing of those on metformin.

Metformin & Vitamin B12: Second Opinion

“I think it lends more support to a practice that is already in place with endocrinologists,” says Minisha Sood, MD, director of inpatient diabetes at the Lenox Hill Hospital, New York, of the study findings. She reviewed the research but didn’t participate in it.

She screens for Vitamin B12 deficiency in her patients ”at least annually if on metformin.” According to Dr. Sood, many endocrinologists do screen for B12 deficiencies in those on metformin. However, she says, many patients with diabetes who are on metformin are cared for by general practice physicians or internists. These patients should ask their doctor’s advice about getting screened for B12 deficiencies, Dr. Sood says.

B12 Deficiency Symptoms & Treatment

Symptoms of B12 deficiency may include numbness, tingling in the feet, and memory problems, Dr. Crandall says. Loss of appetite, weight loss and fatigue can occur. The deficiency typically develops slowly over time, so the regular screening could detect it early.

Treatment includes a weekly B12 injection and then switching to oral vitamins.

The recommended dietary allowance (RDA) for B12 is 2.4 micrograms for those age 14 and older. Foods high in B12 include cooked clams and beef liver, fortified breakfast cereals and fish such as salmon and trout.

Written by: Kathleen Doheny With commentary by Jill Crandall, MD, professor of clinical medicine, Albert Einstein College of Medicine, New York.

A medical group submitted a report to Life Extension Magazine® that provides persuasive data that the AMPK-activating drug metformin may be of significant benefit in protecting the eyes against the threat of blindness from open angle glaucoma.

This report is written with some technical language that may make it challenging for some of our readers to understand.

We choose to publish it with the caveat that a succinct practical suggestion on how to use metformin to potentially reduce glaucoma risk be made in the introduction.

So here is what the medical group that authored this report recommends:

“Those with elevated intraocular pressure (IOP) and/or glaucoma should ask their doctor about prescribing a modest 250 mg-500 mg dose of metformin twice a day after meals as it may have unique beneficial mechanisms in protecting against this blinding disorder.”

We welcome you to read the report beginning on the next page that describes underlying pathologies of open angle glaucoma and how metformin can help to counteract them.

Metformin is a decades-old antidiabetic drug used by millions of type II diabetics all over the world. It is inexpensive, quite commonly prescribed, and its effectiveness in reducing elevated blood glucose is well established.

In addition to its antidiabetic properties, metformin has also been shown to provide a number of other health benefits, including weight reduction, promoting longevity, and reducing cancer incidence, as well as reducing or eliminating chronic pain.2-7 It has calorie restriction mimetic cellular effects such as activating the energy enzyme adenosine monophosphate activated protein kinase (AMPK), and it favorably modulates certain genes thought to be involved in aging.8,9

Now, besides all these reported health effects, a new study reports metformin also reduces the development of open angle glaucoma (OAG).10

Aqueous Humor, Its Functions and Its Relation to Glaucoma Production

Glaucoma is a disease characterized by the increase of intraocular pressure due to various pathologies related to aqueous humor production, circulation, and drainage. In addition, the disease produces subsequent damage to the retina and atrophy of the optic nerve resulting in reduced visual acuity and ultimately leading to blindness.11

Aqueous humor is a transparent, watery fluid that provides nutrition to the front part of the eye. It also transports the metabolic debris produced there to the bloodstream, thus maintaining transparency of the lens and cornea so light rays can pass through cleanly and provide clear vision. Most importantly, it keeps the cornea inflated with hydrostatic pressure, like water in a balloon.

There are many varieties of glaucoma, the most common being open angle glaucoma, in which the angle where the cornea and the iris meet is as wide and open as it should be, but the aqueous humor drainage channels become blocked over time and aqueous humor builds up. This raises intraocular pressure.12,13

As pressure is exerted on the sensitive retina over time, it results in damage to nerve cells and their projection, the optic nerve.11 Once the optic nerve is damaged, it can’t be repaired, even if the raised intraocular pressure is corrected (figure 1).14,15 Abnormally high pressure inside the eye usually causes this retinal and optic nerve damage.

Because open angle glaucoma occurs due to the effects of aging, it may be that the disease is treatable with metformin, because of the drug’s general antiaging properties.

How Metformin Functions in the Body

Metformin works to reduce blood sugar in several ways. It decreases the amount of glucose made by the liver, decreases the amount of sugar absorbed into the body, and makes insulin receptors more sensitive. Metformin does not increase insulin levels as many antidiabetic medications do, which makes it unlikely to cause dangerously low drops in blood sugar.16,17 It’s therefore considered safe for nondiabetics to take.

Let’s examine how metformin works as an antiaging therapeutic agent and extrapolate the findings in terms of its ability to fight glaucoma.

Metformin enhances the activity of an enzyme found within all our cells called adenosine monophosphate-activated protein kinase, or AMPK for short. AMPK activation helps to mimic the beneficial effects of calorie restriction and exercise, the best documented method of slowing and reversing degenerative aging processes and biomarkers of human aging.18

The biological effects of increased AMPK activity include inhibition of fat storage, reduced triglyceride synthesis, and increased glucose uptake into muscle for metabolism.19-27 AMPK activation also enhances destruction of diseased or dying cells as well as removal of intracellular metabolic debris – a method to slow and reverse degenerative aging processes of various organs.9

Further, experiments have shown that metformin, through AMPK activation, promotes the functional activity of the sirtuin family of genes, which is associated with longevity. Scientists have identified several signaling pathways involved in the regulation of aging processes that promote longevity. One of these signals, named p53, controls cell proliferation and is known as a tumor-suppressor gene. Loss of p53 predisposes normal cells to cancer. Metformin helps protect functional p53 so cells are less likely to become cancerous.9,28-31

WHAT YOU NEED TO KNOW

The Benefits of Metformin

Metformin has been prescribed for decades as an effective treatment against type II diabetes. But studies have shown metformin to have a number of other beneficial effects as well. These include promoting longevity, weight loss, and reduced cancer risk, as well as reducing chronic pain.2-7 The drug also has antiaging effects that mimic calorie restriction, and it favorably modulates genes thought to be involved in aging.8,9

Now, new research reveals metformin also reduces the development of open angle glaucoma, a progressive optic neuropathy and a leading cause of blindness.

A University of Michigan study has found metformin to be linked with a 25% reduction in the risk of developing open angle glaucoma. Other medications used to treat type II diabetes did not have a similar benefit. Metformin is the only drug that has an intraocular pressure-reduction therapeutic effect.

Everyone over age 50 would be well-advised to get tested for glaucoma and to ask their physician about possibly taking metformin, which could be preferable to typical antiglaucoma drugs, considering their common side-effects and lack of antiaging properties.

Metformin’s Inflammation-Reducing Property

Nuclear factor-kappa B (NF-kB) is an internal cell signal that induces chronic inflammation responsible for many diseases, from cancer to heart attack, neurodegenerative diseases and even glaucoma.32-35

NF-kB activation is blamed for many chronic diseases that ravage us as we age. Metformin produces higher AMPK activity which decreases expression of NF-kB.36

By blocking NF-kB, metformin is thought to promote longevity by inhibiting systemic inflammatory processes in the body, which play havoc in all our vital organs including the brain and heart, as well as the eyes.

A recent study has found that metformin relieves neuropathic and other pain by decreasing the activation of microglial cells in the spinal cord that are an integral part of the central nervous system and its proper functioning as discussed below.6

Common characteristics for many neurodegenerative diseases include changes in glial cells, progressive neuronal loss, increased inflammation and oxidative stress.37 Thus decreasing the activation of glial cells in the brain is one promising approach to reducing the inflammation in the brain responsible for various neurodegenerative diseases including Parkinson’s and Alzheimer’s disease. This is exactly what a group of researchers found in an animal model of neuropathic pain treated with metformin—glial cell activation was decreased and chronic pain was reduced.6 We believe these findings may have implications to decrease neuropathic pain in thousands of patients treated with the expensive drug gabapentin (Neurontin®).

Glial cells have multiple functions:38,39

They surround neurons and hold them in place.

They supply nutrients and oxygen to neurons.

They insulate one neuron from another.

They destroy pathogens and remove dead neurons with various processes, including production of inflammatory cytokines that, besides attacking the invading microorganism, can promote neurodegenerative diseases.

They transport the brain’s interstitial fluids between neurons to the cerebrospinal fluid, through drainage channels they create called glymphatics.

They play a role in synapse formation and the transmission of electrical signals from one nerve cell to another, especially in memory centers of the brain. Basically, glial cells are caregivers to nerve cells and facilitate nerve cell activity in the central nervous system and maintain a homeostatic milieu for nerve cells to function properly.

Now let us examine how metformin can help fight glaucoma and age-related neurodegenerative diseases related to glial cell pathology.

Originally marketed as an agent for type II diabetes, metformin has been found to have a number of other uses in clinical practice, including, in one study, the ability to decrease the activation of glial cells in the spinal cord.6Researchers reported complete resolution of suffering in some rats with induced neuropathic pain. This study reveals the impact of metformin on the nervous system glial cells, which are believed to be associated with chronic pain. If that is the case, is it possible that metformin can protect other parts of the nervous system, such as the retinal ganglion cells, by inhibiting the activity of glial cells that produce inflammatory cytokines that are toxic to neurons? This would also explain our finding and the findings of other scientists that those on metformin have better cognition with reduction in dementia.40,41 In our practice we routinely prescribe metformin for people over the age of 50 to be taken twice daily after meals to prevent future neurodegenerative diseases and aging.

Christian de Duve, 1974 Nobel Laureate in physiology or medicine, coined the term autophagy (meaning “self-eating”) in 1963. This year, biologist Yoshinori Ohsumi, of the Tokyo Institute of Technology, has been awarded the Nobel Prize in physiology or medicine for his discoveries in autophagy, the process whereby a cell recycles part of its own cellular debris (cellular house cleaning).

Scientists had been aware of autophagy for decades, but knew little about how it worked—until Ohsumi’s pioneering experiments in the 1990s. It’s important because autophagy can eliminate invading intracellular bacteria. Disrupted autophagy has been linked to Parkinson’s and Alzheimer’s disease, type II diabetes and other disorders that particularly affect the elderly.

We know that metformin enhances autophagy, which is how it reduces diseases of aging such as Parkinson’s and Alzheimer’s, and may reduce the incidence of glaucoma. This is one more reason to prescribe metformin.

How Does Metformin Reduce Glaucoma?

A recent study found that metformin reduces the intraocular pressure of primary open angle glaucoma.10 Open angle glaucoma is a progressive optic neuropathy characterized by loss of retinal ganglion cells and optic nerve atrophy.42 It’s the most common form of glaucoma and is often asymptomatic and may even go undetected for a while.43 By the time vision is noticeably impaired, the loss is irreversible, because once the nerve cells are dead in the retina with degeneration of the connected nerve fibers, nothing can restore them.

Open angle glaucoma is a manifestation of aging along with other neurodegenerative diseases. Normally, through autophagy, our cells purge themselves of accumulated debris, often called “cellular metabolic junk.” Autophagy is a natural mechanism that disassembles cells’ unnecessary or dysfunctional components as they age and lose their function. But over time, our cells lose this housekeeping ability.44,45 Metformin has been shown to promote this process.46

According to a study at the University of Michigan, metformin was associated with a 25% reduction in the risk of developing open angle glaucoma. They also found that other oral antidiabetic medications used to treat type II diabetes did not confer a similar risk reduction. Metformin is the only drug endowed with this intraocular pressure-reduction therapeutic effect.

This retrospective cohort study was based on longitudinal data from more than 150,000 patients with type II diabetes and no preexisting record of open angle glaucoma. Forty percent filled at least one metformin prescription. During the 10-year study period, 5,893 (3.9%) of the patients of a large health care network developed the disease. The researchers compared users of metformin with nonusers, analyzing the data by means of regression modeling. Each model demonstrated substantial reductions in open angle glaucoma risk among those using metformin. In two years, a diabetic patient taking a daily 2,000 mg dose of metformin would have a 20.8% reduction in open angle glaucoma risk, compared with a diabetic patient who had no metformin exposure.10

Metformin was associated with a 25% reduction in the risk of developing open angle glaucoma.

Glaucoma is the second leading causes of blindness in the world.1 It is estimated that in excess of 2.5 million people have glaucoma in the United States, and that more than 120,000 people are legally blind from the disease.42 Many people who have it aren’t aware of it. Blindness from glaucoma is six to eight times more common in African Americans than Caucasians, and, after cataracts, is the leading cause of blindness among them.43 We advise all those over the age of 50, especially African Americans and women, to get their eyes tested for glaucoma and ask their physician if it is appropriate to start taking metformin, not as an antidiabetic, but for its antiaging, antiglaucoma properties. Women have longer life expectancy and are more likely than men to develop age-related eye diseases like glaucoma.47

There are dozens of drugs available to treat glaucoma.48,49 Many of them have systemic complications and lack the antiaging effect of metformin on the rest of the body. Wouldn’t it make sense to prescribe metformin to prevent glaucoma and at the same time delay and/or reverse the ravages of aging?

Researchers at the University of Michigan Kellogg Eye Center have suggested a clinical trial protocol in which newly diagnosed glaucoma patients would be randomized to receive either an IOP (intraocular pressure)-lowering drug plus metformin or a glaucoma drug plus a placebo.50 From our point of view, a randomized clinical trial which might take decades may not be needed. Metformin is inexpensive, widely used to treat type II diabetics, and has hardly any adverse effects.

Summary of How Metformin Wards Off Glaucoma

Given how aqueous humor is formed, how it circulates and exits the eye, there are numerous possible explanations for how metformin works. It may act to reduce open angle glaucoma risk at multiple levels, which need to be further examined. The possible mechanisms are:

Metformin, by inhibiting an inflammatory reaction and its related cytokines, may reduce aqueous humor production by ciliary processes, and bring it to stability.

By promoting autophagy, it may prevent exfoliated cells from blocking the aqueous humor drainage channels of the meshwork and the Schlemm’s canal.

By AMPK activation, it may reverse the biomarkers of human aging in the uveal aqueous humor production structures and transportation channels of aqueous humor.

Due to increased AMPK activation, as the aqueous humor circulates, it comes in contact with trabecular meshwork and may cleanse the glycation around the endothelial cells of the trabecular meshwork, thus allowing the aqueous humor to pass to exits without resistance.

Metformin in the aqueous humor may cleanse and open the pores in the Schlemm’s canal and uvea-scleral pathways by activation of AMPK, resulting in autophagy within the disease-afflicted lining cells of trabecular meshwork.

By autophagy, it may effectively cleanse the platelet clumps and lipid deposits in the trabecular meshwork and the Schlemm’s canal that facilitates the easy drainage of the aqueous humor without increasing intraocular pressure.

Metformin protects the functional p53 gene while repressing and/or blocking the pro-inflammatory NF-kB by reversing or inhibiting inflammatory process in the body, including the eyes.29,30,36 By reduction of inflammatory cytokines, it may protect the retina and prevent the degeneration of ganglion cells and optic nerve fibers, thus reducing the chances of blindness.

Metformin reduces resistance to insulin, thus helping uptake and metabolism of circulating sugar, and preventing the adverse effects of hyperglycemia such as glycation—the bonding of a protein or lipid molecule with a sugar molecule.16,17,51

Loss of ganglion cells in the retina is a leading cause of blindness in open angle glaucoma.42 This could be prevented with metformin by decreasing activation of glial cells in the retina and optic nerve.

FDA Approves Human Trials on Metformin Antiaging Effects

Further studies will point out the multiple ways metformin reduces the incidence of open angle glaucoma in older people as it provides antiaging protection in other organs and tissues and possibly even prevents or reduces the incidence of age-related macular degeneration.

Interestingly, the FDA’s approval of the first human trials to see if metformin can protect against diseases of aging was headlined in news media reports. We hope this study includes the drug’s effect on the eyes of the aging population.

For decades, Life Extension has discussed the antiaging effects of metformin. Finally, the FDA has heard their call. This study may take decades to reveal its findings, hence our practice has started advocating for metformin use for people over the age of 50 to promote good health and reverse, inhibit, or stop the ravages of aging.

Although it can cause lactic acidosis if taken in doses that are much larger than required for treatment, metformin is essentially very safe. The public should demand that the FDA approve metformin for use without prescription as an over-the-counter medication, both in oral form and as ophthalmic drops.

This will reduce medical cost and improve the health of many, with reduction in age-related diseases (which cost billions to care for). It will also bestow longevity, with probable reductions of neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and at the same time provide good eyesight. Until that happens, the best alternative is for patients to ask their physicians to prescribe metformin for them and put it in writing that they, the patients, will not hold their doctors responsible for any untoward effects. Those with elevated intraocular pressure and/or glaucoma should ask their doctor about prescribing a modest 250 mg–500 mg dose of metformin twice a day after meals.

When developed, metformin ophthalmic drops, besides preventing open angle glaucoma, may also prevent or delay the development of age-related macular degeneration and diabetic retinopathy, and restore good vision to the aging population inexpensively. We appeal to the pharmaceutical industry to develop metformin ophthalmic drops with other adjuvant therapeutic agents to treat various eye diseases such as open angle glaucoma, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy and uveitis.

Researchers at University of California San Diego School of Medicine have identified a previously unknown mechanism that helps fortify the structure and tight junctions between epithelial cells — a basic cell type that lines various body cavities and organs throughout the body, forming a protective barrier against toxins, pathogens and inflammatory triggers. Breaches of this barrier can provoke organ dysfunction and development of tumors.

The findings, published online in the current issue of eLife by senior author Pradipta Ghosh, MD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues, helps illuminate why the widely prescribed anti-diabetic drug Metformin has repeatedly been shown to not only protect epithelial integrity in the face of stressors like inflammation, sepsis, hypoxia and harmful microbes, but also appears to prevent cancer.

Virtually all cell types possess cell polarity — the asymmetrical organization of their components and structures that makes it possible for them to carry out specialized functions. In epithelial cells, polarity determines how they form barriers. Loss of epithelial polarity impacts organ development and function and can initiate cancers.

The stress-polarity pathway, discovered and described in 2006 and 2007, is a specialized pathway mobilized only during periods of stress. It is orchestrated by a protein-kinase called AMPK that protects cellular polarity when epithelial cells are under energetic stress and an activator of AMPK called LBK1.

“The latter is a bona fide tumor suppressor,” said Ghosh. Mutations in LBK1 have been linked to cancers and loss of cell polarity. While the question of exactly how the energy-sensing LKB1-AMPK pathway maintains cell polarity during stress remained unknown for more than a decade, evidence accumulated that Metformin, an activator of the LKB1-AMPK pathway and a frontline treatment for type 2 diabetes, has beneficial effects on the epithelial lining and can potentially prevent cancer.

The new research, said Ghosh, provides “mechanistic insights into the tumor suppressive action of Metformin and the LKB1-AMPK pathway at a higher resolution.” Specifically, she and colleagues discovered that the stress-polarity pathway requires a key effector of AMPK — a protein called GIV/Girdin.

In cultured polarized epithelial cells, the authors demonstrated that AMPK and its activator Metformin exerted much of their beneficial effects via phosphorylating GIV and directing GIV to the tight junctions of the epithelial layer. Without such phosphorylation and/or targeting, the beneficial effects of AMPK, and its activator Metformin, were virtually abolished and the epithelial barrier became “leaky” and eventually collapsed. Mutants of GIV found in colon cancer that specifically abolish AMPK’s ability to phosphorylate GIV could trigger tumor cell growth in 3D matrigel.

“In summary, by identifying GIV/Girdin as a key layer within the stress-polarity pathway we’ve peeled another layer of the proverbial onion,” Ghosh said. “In the process, we’ve provided new insights into the epithelium-protecting and tumor-suppressive actions of one of the most widely prescribed drugs, Metformin, which may inspire a fresh look and better designed studies to fully evaluate the benefits of this relatively cheap medication.”

MICHAEL RAE eats 1,900 calories a day, 600 fewer than recommended. Breakfast is a large salad, yogurt and a “precisely engineered” muffin. In a mere 100 calories this miracle of modern gastronomy delivers 10% of Mr Rae’s essential nutrients. Lunch is a legume-based stew and another muffin. Dinner varies. Today he is looking forward to Portobello mushroom with aubergine and sage. There will be a small glass of red wine. He has been constraining his diet this way for 15 years.

In some animals calorie restriction (CR) of this kind seems to lessen the risk of cancer and heart disease, to slow the degeneration of nerves and to lengthen life. Mr Rae, who works at an anti-ageing foundation in California, thinks that if what holds for rodents holds for humans CR could offer him an extra seven to 15 years of healthy life. No clinical trials have yet proved this to be the case. But Mr Rae says CR dieters have the blood pressure of ten-year-olds and arteries that are clean as a whistle.

The “profound sense of well-being” Mr Rae reports might seem reward enough for his privations. But his diet, and the life extension he thinks it might bring, are also a means to an end. Mr Rae, who is 45, thinks radical medical advances that might not merely slow but stop, or reverse, ageing will be available in the not-too-distant future. If CR gets him far enough to benefit from these marvels then a few decades of deprivation might translate into additional centuries of life. He might even reach what Dave Gobel, boss of the Methuselah Foundation, an ageing-research charity, calls “longevity escape velocity”, the point where life expectancy increases by more than a year every year. This, he thinks, is the way to immortality, or a reasonable approximation thereof.

That all remains wildly speculative. But CR is more than just an as-yet-unproven road to longer human life. Its effects in animals, along with evidence from genetics and pharmacology, suggest that ageing may not be simply an accumulation of defects but a phenomenon in its own right. In a state of nature this phenomenon would be under the control of genes and the environment. But in a scientific world it might in principle be manipulated, either through changes to the environment (which is what CR amounts to) or by getting in among those genes, and the metabolic pathways that they are responsible for, with drugs.

A treatment based on such manipulation might improve the prospects of longer and healthier life in ways that drugs aimed at specific diseases cannot match. Eileen Crimmins, a researcher at the University of Southern California in Los Angeles, points to calculations which show that the complete elimination of cardiovascular disease would add only 5.5 years to overall life expectancy in America, and removing deaths from cancer would add just 3.2 years. This is because diseases compete to kill people as they age; if one does not get you the next will. According to Dr Crimmins, increasing life expectancies much beyond 95 would require an approach that held the whole pack at bay, not just one particular predator.

Something which slowed ageing down across the board might fit the bill. And if it delays the onset of a range of diseases it might also go some way to reducing the disability that comes with age. An ongoing long-term study at Newcastle University has been looking at the health and ageing of nearly 1,000 subjects now aged 85. At this point they have an average of four to five health problems. None of them is free from disease. Most researchers in the field scoff at talk of escape velocities and immortality. But they take seriously the prospect of healthier 85 year olds and lifespans lengthened by a decade or so, and that is boon enough.

Indications of immortality

Before discovering whether anti-ageing drugs might be able to deliver such things, though, researchers need to solve a daunting regulatory conundrum. At the moment the agencies that allow drugs to be sold do not consider ageing per se to be an “indication” that merits therapy. It is, after all, something that happens to everyone, which makes it hard to think of as a disease in search of a cure, or even a condition in need of treatment. Unless ageing is treated as an indication, anti-ageing drugs can’t get regulatory approval. And there’s little incentive to work on drugs you can’t sell.

If regulators were to change their stance, though, the interest would be immense. A condition that affects everyone is as big a potential market as can be imagined. And there are hints that the stance may indeed be changing. Two existing drugs approved for other purposes—metformin, widely used and well tolerated as a treatment for diabetes, and rapamycin, which reduces the risk of organ transplants being rejected—look to some researchers as though they might have broad anti-ageing effects not unlike those claimed for CR. In 2014 a study of 90,000 elderly patients with type 2 diabetes found that those receiving metformin had higher survival rates than matched non-diabetic controls. Other work has shown its use is associated with a decreased risk of cancer.

Scientists at the Institute for Ageing Research at the Albert Einstein College of Medicine, in New York, want to mount a trial of metformin in elderly subjects to see whether it delays various maladies (and also death). If that turns out to be the case, it will go a long way to showing that there is a generalised ageing process that can be modulated with drugs. Nir Barzilai, one of the researchers involved, says an important reason to do the trial is to have an indication against which next-generation ageing drugs can be assessed by regulators.

This sort of interest seems to be triggering a change of tone at America’s Food and Drug Administration over whether it might approve an anti-ageing drug. The regulator is thinking about when a broad, and so far unprecedented, claim of anti-ageing might be considered to be supported by the evidence; it is “looking forward to seeing this area of science evolve”. In the dry language of a government agency these are encouraging words.

If an unregulated diet can do the trick, why does the world need drugs? Three reasons. One is that taking a few pills a day will be easier for most than subsisting on low-calorie muffins and salad. A second is that companies can make money making pills and will compete to create them. A third is that pills may work better than diets. Dr Barzilai, who is in the pill camp, points out that CR works less well in primates than other mammals, and that people with low body-mass indices, a natural condition for those restricting their calories, are in general more likely to die. Those who do well on CR, he says, are likely to be a subset benefiting from the right genetic make-up. His hope is that a range of targeted therapies might allow everyone to get the benefits.

If they do, it will be by inducing changes in metabolism. It has been known for 20 years that altering the gene daf-2 in roundworms slows their ageing and doubles their lifespans; another gene, daf-16, is now known to be required for this to work. Equivalent genes in humans are in charge of the cell-surface receptors for insulin and insulin-like growth factor 1, hormones with key metabolic roles. The human equivalent of daf-2 seems to be turned on by CR. Very long-lived people have been found to share particular variants of the human version of daf-16.

Another effect of CR is that it deactivates mTOR, a protein that helps pass signals from growth hormones to the parts of the cell involved in protein synthesis. It plays a role in regulating the cell’s metabolism, division and growth, and prevents the breakdown of damaged cells. When food is abundant mTOR stimulates cell division and growth.

Throwing the switch

These lines of research suggest that in the animals where CR works well it switches cells from a regime where they concentrate on growing to one where they concentrate on their own repair. In that second mode damage to cells accumulates more slowly, which means they age less. Drugs that seem to have an effect on ageing achieve some of the same shift. Metformin acts on a number of hormone receptors which are also affected by CR (see chart); rapamycin works on a pathway that gets its name from a protein that is the “target of rapamycin”: mTOR. Reducing the function of mTOR extends life in yeast, worms and flies. In 2009, work in a number of laboratories showed that rapamycin can extend the lifespan of middle-aged mice by 14%.

Alexander Zhavoronkov, the boss of Insilico Medicine, a longevity firm, says he is testing rapamycin on himself (self experimentation does not seem uncommon in the field). But he warns it is necessary to have a significant knowledge of biomedicine to do so safely. The drug has serious side effects; rodents treated with it suffer from insulin resistance and it suppresses the immune system. That’s good when preventing the rejection of organ transplants—the drug’s current medical use—but not so good in otherwise healthy people. One idea is that low doses might preserve the drug’s benefits while limiting its side-effects.

There are other drugs, though, that target the same pathway with fewer downsides. One of these, resveratrol, caused a great deal of excitement among longevity researchers a few years ago because it kept mice on rich diets youthful. A lot of the initial interest has waned since it was discovered to be less helpful in mice that are not overweight, but it is still being investigated as an Alzheimer’s treatment.

David Sinclair of the Harvard Medical School, who was part of the initial enthusiasm, describes it as a “dirty” drug, in that it has a number of targets within the cell. Among them are a set of proteins known as sirtuins which appear to be activated by resveratrol. Dr Sinclair created a company, Sirtris Pharmaceuticals, to investigate the potential of drugs aimed at these targets. GSK, a British pharma company which bought Sirtris in 2008, continues this work, though to date it has not yielded as much as was once hoped.

Sirtuins may act as metabolic sensors, and a number are found exclusively in the mitochondria, the structures in cells that look after respiration and which are central to the evolving concept of cellular ageing. Thomas von Zglinicki of Newcastle University says ageing cells are characterised by mitochondrial damage and have difficulty recycling damaged or broken cell machinery. They produce pro-inflammatory factors called cytokines which move neighbouring cells to senescence; chronic progressive inflammation of this sort drives various age-related diseases.

João Passos, also at Newcastle University, says cells from which mitochondria are removed start to look more like young cells and stop secreting cytokines. Other work has shown that killing off mitochondria can mimic some of the effects of drugs that activate mitochondrial renewal—such as rapamycin. Faster turnover of mitochondria seems to improve their functioning.

Data against death

Such discoveries in cell and molecular biology have perked up commercial interest in longevity. So too has data from the hundreds of thousands of human genome sequences. Dr Zhavoronkov’s Insilico Medicine, based in Baltimore, is using machine learning on vast piles of published genomic data to work out the differences between the tissues of young and old people and to look at how patterns of gene expression evolve as people age. It then looks in drug databases for molecules that might block the effects of the genes it thinks matter.

The force to be reckoned with in this field, though, is Craig Venter, a pioneer in gene sequencing. In 2013 he founded Human Longevity Inc (HLI), based in San Diego. Like Insilico, HLI wants to sift through genomic data; but it does so on a vastly larger scale, generating the genomic data itself and matching them with details of physiology and appearance. Dr Venter hopes this will allow the company to unpick the genetics of longevity and predict how long people will live. Research at HLI has already found that some genetic variations are absent in older people, a finding that implies they might be tied to shorter lifespans. Companies such as Celgene and AstraZeneca that work in drug discovery have made deals to collaborate with HLI. Dr Venter says HLI may eventually move into the drug business itself.

For those who cannot wait for drugs, HLI has a high-end “wellness” service called the Health Nucleus. At prices starting from $25,000 it will give a customer a constellation of cutting-edge tests, including a full sequence of both his genome and a battery of tests for the signs of cancer, Alzheimer’s and heart disease. Lots of tests means lots of possibilities for “false-positive” results; but the affluent clients of Health Nucleus may worry less about follow-ups that reveal false alarms than other people do.

In 2013 Google (now Alphabet) started a venture called the California Life Company, or Calico, to take a “moonshot” approach to anti-ageing; the company has said it will invest up to $750m in the venture. Calico is a drug-development company much more willing to talk about its world-leading scientists, such as Cynthia Kenyon, a worm biologist, and the track record of its boss, Arthur Levinson, who used to run Genentech, a biotech giant, than about what it is actually doing. But it has announced a series of collaborations, the most significant of which is a ten-year R&D deal with AbbVie, a pharma company based in Chicago, focused on cancers and degenerative nerve conditions.

Degeneration leads to thoughts of regeneration. Even the most enthusiastic adherents of slowing down ageing by means of diet or pharmacology have to admit that it will not keep people going forever. At best it might allow them to age as slowly as the slowest-ageing people do naturally. And that makes it unlikely, even at its most effective, to increase lifespans beyond 120, because that seems to be more or less the natural upper limit to a human lifespan. Improvements in medicine and welfare mean that there are many more people in their 90s and 100s round the world today than there used to be. The number of people in their 130s, though, remains stubbornly at zero.

To do something about this means not just slowing ageing but stopping or reversing it, either by causing bits of the body to rejuvenate themselves or by removing and replacing them. This is where stem cells come in. They play an important role in the repair and regeneration of tissue; they can be induced to differentiate into a range of specialised cells, and thus to replace cells that are worn out or used up. Regenerative therapies seek to supplement this repair using stems cells from elsewhere. They might be taken from frozen samples of placentas; they might be created from existing body cells.

Many stem-cell therapies are moving rapidly towards clinical trials under the rubric of “regenerative medicine”. Both Calico and HLI are active in the field. Research has shown that nerve cells grown from human embryonic stem cells and transplanted into rats with the equivalent of Parkinson’s disease proliferate and start to release dopamine, which is what such rats and people lack. Roger Barker of the University of Cambridge recently treated a man with Parkinson’s this way. ReNeuron, based in Bridgend in Wales, is in trials designed to discover the efficacy of stem cells as a treatment for disabilities brough on by stroke. Despite the risks of unregulated therapies, hundreds of clinics around the world are already rushing to offer “treatments” for the diseases of age. This is unsurprising. It is historically an area rich in hope, hype and quackery, and it will take some time for well-founded research to clean the stables—if, indeed, it can.

Another regenerative possibility flows from studies which find signs of rejuvenation in elderly animals exposed to the blood of younger animals. Infusions of young people’s blood plasma are being tried out on some Alzheimer’s patients in California. A startup called Ambrosia, based in Monterey, recently began “trials” of such a therapy with healthy participants who pay $8,000 to take part; critics say they are so lacking in controls that they are unlikely to generate any useful information. If particular genes are beneficial then gene therapy, or gene editing, could prove to be fertile ground; work to this end has begun in mice. And some won’t wait. Elizabeth Parrish, the boss of a biotech company called BioViva, claims she has already given herself an anti-ageing gene therapy.

Beyond this horizon

The extent to which any of this technology will help will depend on how old those it is used on are when it comes into its own. The scope for radically changing the lifespan of a 65-year-old is much smaller than that of a 20-year-old, let alone an embryo. But the amount that is lost by getting things wrong goes up in exactly the same way.

The idea that radical biotechnology can lead to longer lifespans than that of Jeanne Calment, a French woman whose recorded lifespan of 122 years has never been bettered, seems at best a plausible speculation. To say—as Aubrey de Grey, a noted cheerleader for immortality, has done—that the first person to live to 1,000 has probably already been born seems utterly outlandish. But thinking through Calment’s life might give you pause. When she was born, in 1875, the germ theory of disease was still a novelty and no one had ever uttered the word “gene”. When she died in 1997 the human genome was almost sequenced. All of modern medicine and psychiatry, barring general-purpose anaesthesia, was developed during her lifetime. If a little girl born today were to live as long—and why should she not?—she would see the world of 2138. The capabilities of medicine at that point will surely still be limited. But no one can guess what those limits will be.